MicroRNA-16 is putatively involved in the NF-κB pathway regulation in ulcerative colitis through adenosine A2a receptor (A2aAR) mRNA targeting

Abstract

MicroRNAs (miRNAs) act as important post-transcriptional regulators of gene expression by targeting the 3′-untranslated region of their target genes. Altered expression of miR-16 is reported in human ulcerative colitis (UC), but its role in the development of the disease remains unclear. Adenosine through adenosine A2a receptor (A2aAR) could inhibit nuclear factor-kappaB (NF-κB) signaling pathway in inflammation. Here we identified overexpression of miR-16 and down-regulation of A2aAR in the colonic mucosa of active UC patients. We demonstrated that miR-16 negatively regulated the expression of the A2aAR at the post-transcriptional level. Furthermore, transfection of miR-16 mimics promoted nuclear translocation of NF-κB p65 protein and expression of pro-inflammatory cytokines, IFN-γ and IL-8 in colonic epithelial cells. Treatment with miR-16 inhibitor could reverse these effects in cells. The A2aAR-mediated effects of miR-16 on the activation of the NF-κB signaling pathway were confirmed by the A2aAR knockdown assay. Our results suggest that miR-16 regulated the immune and inflammatory responses, at least in part, by suppressing the expression of the A2aAR to control the activation of the NF-κB signaling pathway.

Increased M1 macrophages in young miR‐15a/16−/− mice with tumour grafts or dextran sulphate sodium‐induced colitis

“…MiR-16 can negatively regulate the expression of the adenosine A2a receptor (A2aAR), which inhibits the NF-κB signalling pathway in inflammation. 22 Thus, the transfection of miR-16 mimics promotes nuclear translocation of NF-κB p65 protein and expression levels of proinflammatory cytokines IFN-γ and IL-8 in colonic epithelial cells. 23 Moreover, miR-16 promotes the NF-κB-regulated transactivation of the IL-8 gene by suppressing the silencing mediator for retinoid and thyroid hormone receptor.…”

“…MiR‐16 overexpression is also involved in promoting M1 macrophages. MiR‐16 can negatively regulate the expression of the adenosine A2a receptor (A2aAR), which inhibits the NF‐κB signalling pathway in inflammation . Thus, the transfection of miR‐16 mimics promotes nuclear translocation of NF‐κB p65 protein and expression levels of proinflammatory cytokines IFN‐γ and IL‐8 in colonic epithelial cells .…”

Purinergic drug targets for gastrointestinal disorders

“…MicroRNA-16 in human UC regulates the increase in inflammatory responses by suppressing the expression of the A 2A AR to control the activation of the NF-κB signalling pathway (Tian et al, 2016; Figure 4). MicroRNA-206 has a pro-inflammatory role in UC by downregulating A 3 AR expression and activating NF-κB signalling (Wu et al, 2017).…”

“…( G ) Correlation between miR-16 and A 2A AR protein expression, miR-16 expression showed a strong negative correlation with A 2A AR protein level in active UC inflamed sigmoid tissues (n = 28, Pearson correlation r = − 0.438, P  < 0.05). (Reproduced from Tian et al, 2016, with permission (Creative Commons Attribution 4.0 International License).…”

Therapeutic potentials of adenosine receptors agonists and antagonists in colitis; Current status and perspectives

“…Consistent with this hypothesis, colitis patients express high levels of microRNA‐16 (miR‐16) which is able to decrease the expression of A2a adenosine receptors, resulting in high expression of NF‐κB and other proinflammatory molecules including IFN‐γ and IL‐8 in colonic epithelial cells. Treatment of cells with miR‐16 inhibitor improves inflammatory processes in colitis significantly, supporting the protective role of A2a adenosine receptors activations in these patients (Tian et al, ). T‐cell mediated colitis in animal models is reconstituted with pathogenic CD45RB (high) CD4+ splenic T cells which can be attenuated by co‐transfer of regulatory subsets of Th cells including CD45RB(low) CD4+ T cells (Powrie, Carlino, Leach, Mauze, & Coffman, ).…”